Aneuploidy and chromosomal aberrations are common features of human neuroplasms. Genomic instability, or the tendency for mitotic errors to create chromosomal duplications, losses, and translocations has long been recognized as a major mechanism of tumorigenesis. The study of genomic instability promises new insights into cancer treatment. Recently, significant advances have been made in the understanding of the molecular details of the regulation of mitosis. Securin is a protein that functions to ensure accurate distribution of chromosomes to daughter cells by inhibiting anaphase progression until all chromosomes are properly aligned at metaphase. When cells are manipulated to over-or under-express securin they develop chromosomal abnormalities and micronuclei. Such micronuclei are frequently seen in neurological tumors, especially oligogendrogliomas. Another protein, Emi1, recently discovered by the Peter Jackson Laboratory, is involved in S phase activation and mitotic control. Emi1 blocks the degradation of securin by inhibiting its ubiquitination, but also directly binds to securin. Over-expression of Emi1 causes an abnormal prometaphase block and abnormal mitotic spindle formation. We hypothesize that the direct interaction of Emi1 and securin mediates this effect causing genomic instability. Hct116 colon carcinoma cells are a diploid cell line ideal for mitotic studies. I will use these cells as a tool to study the control of genomic stability by Emi1 and securin. I will also address the possible role of Emi1 and securin in the genesis of neurological tumors. The proposed research will specifically address the following questions. Do endogenous Emi1 and securing interact directly in cells, and if so, during which stage(s) of the cell cycle? Is the Emi1-securin interaction localized within the cell? Which functional domains of Emi1 and securin are important in determining their interaction? Does Emi1 misexpression cause spindle abnormalities or chromosomal missegregation, and is securin required for this effect? Does over- or under-expression of Emi1 produce chromosomal aberrations such as deletions or duplications? If so, do specific cytogenetic abnormalities occur? Does Emi1 over-expression induce cellular transformation, or cooperate with known oncogenes such as ras, myc, or securin, in inducing transformation? Does Emi1 misexpression occur in specific tumor types, including neurological tumors? Does Emi1 expression positively or negatively correlate with securin expression in tumors? Does Emi1 or securin expression correlate with activation of the cyclin D/Rb/E2F pathway in tumors? I will pursue an academic career in neuropathology and will apply the knowledge and experience gained from the proposed studies to translational neuro-oncology research.